Treatment of female sexual dysfunction

ABSTRACT

A treatment for female sexual dysfunction by the provision of at least one dopamine mimetic odorant, the odorant being capable of causing a physiological effect in, or from, the human brain which ameliorates the dysfunction, particularly Hypoactive Sexual Desire Disorder (HSDD), and delivery systems therefore.

The present invention relates to the treatment of female sexualdysfunction and is directed particularly, but not exclusively, toHypoactive Sexual Desire Disorder.

The term female sexual dysfunction is a term used for various disordersof the sexual process in women and is categorised by pain associatedwith intercourse or by a disturbance in the process that forms thesexual response cycle. The sexual response cycle is divided into fourdistinct phases consisting of (i) the desire phase; (ii) the arousal orexcitement phase; (iii) the orgasmic or plateau phase; and (iv) theresolution phase.

The (i) desire phase involves fantasies about and the desire to havesexual activity. The lack of such fantasies and desires and the generallack of receptivity to sexual activity is referred to as HypoactiveSexual Desire Disorder (HSDD). This disorder may cause personal distressor interpersonal difficulties.

The (ii) arousal or excitement phase is typically evidenced by vaginallubrication as a consequence of increased fluid production through bloodflow. Dysfunction in this cycle is termed Sexual Arousal Disorder andmanifests itself as an inability to obtain or maintain sufficient andadequate vaginal lubrication or a swelling response during this phase.This disorder is commonly associated with post-menopausal women and maycause extreme personal distress and interpersonal difficulties. Thatsaid, all women may be affected by this disorder at some stage in theirlives.

The final phase, (iv) the resolution phase, is when the blood flowreturns to normal and muscle tension and tightness dramaticallydecrease.

There are further forms of sexual dysfunction, such as female orgasmicdisorder which is described as a persistent or recurrent delay orabsence of an orgasm following the normal sexual excitement phase. Thisdisorder may be present in women as a result of surgery or hormonedeficiencies and/or present in women who have never achieved an orgasm.

Additionally, there are sexual pain disorders and these generally fallinto one of two categories. The first category is dyspareunia andconcerns genital pain associated with sexual intercourse. Pain can beassociated with initial penetration or during deep thrusting, resultingin an intensity of pain which makes the prolonging of intercourse nearimpossible. The other category of sexual pain disorder is vaginismus andthis is defined as the recurrence or persistent involuntary spasm orcontraction of the perineal muscles that surround the outer third of thevagina when the insertion of any object is attempted.

The female sexual dysfunction which is of principal concern to thepresent invention is the treatment of Hypoactive Sexual Desire Disorder(HSDD). Of all female sexual problems, a lack of interest in sexualactivity is most prevalent, affecting 30% of women.¹¹ Laumann E O, Paik A, Rosen R C. Sexual dysfunction in the UnitedStates. JAMA 1999; 281: 537-544.

HSDD concerns sexual desire and this desire has two mainmanifestations—“proceptivity” (seek out and/or initiate sexual activity)and “receptivity” (accept sexual activity when offered). Thesemanifestations are analogous to an appetite for food, the analogy beingthat when we feel hungry we seek out food, or when we do not feel hungrywe do not seek out food until we see it tasteful and attractivelypresented. For many women, the complaint of lack of sexual desire isfound, typically, to mean a lack of proceptivity, the woman maintainingreceptive sexual behaviour.

Indeed the “appetite” phase of sexual functioning can be conceptualisedin two components—designated “sexual drive” and “sexual desire”.² Inthis dichotomisation, the term “sexual drive” means the biological drivethat generates proceptivity and receptivity. This drive is omnipotent inthat it can be satisfied by a variety of behaviour (e.g. sexual activitywith a partner, masturbation, sexual fantasies). Conversely, the term“sexual desire” is used to mean a desire for a specific behaviour. Ineffect, “sexual desire” is focused sexual drive.² Riley A. Problems of the sexual response cycle. The Diplomate, TheJournal of the Diplomats of the Royal College of Obstetricians andGynascologists, 1997; 4: 270-275.

It will be appreciated that the physiology of sexual drive in women isnot well understood. Sexual drive is thought to be generated in specificnuclei of the hypothalamus, often called collectively the “sex drivecentre”. These nuclei have positive (sexually enhanced) and negative(sexually inhibiting) influences from other centres of the centralnervous system mediated through neurotransmitters and neurohormones.

Treatment of HSDD may be two fold. Firstly and importantly, a correctdiagnosis of HSDD would need to be made. Once a physician is comfortablethat there is no organic cause and that any severe medical conditions,such as diabetes or heart disease, were correctly treated, it would thenbe necessary to discuss interpersonal difficulty with a partner. OnceHSDD is diagnosed, the condition would be amiable to treatment withsexual therapy. A further treatment may be by hormone therapy.

Oestrogen therapy is commonly used in the pharmacological treatment ofsexual dysfunction in women. Oestrogen-based therapies are generallyused to increase mucus production, to provide vasodilatory effects, orto increase the general health of the vagina.³ In such treatments,oestrogen is administered orally, by injection or topically. With oraladministration, the oestrogen concentration encountered by the liver isgenerally four to five times greater than the oestrogen levels inperipheral blood. This effect may lead to an undesirable increase in theproduction of certain coagulation factors and renin substrates in theliver. Oestrogen administered by injection avoids this effect in theliver. However, all oestrogen-based therapies are known to increase therisk of endometrial hyperplasia, endometrial cancer and breast cancer intreated individuals. Due to the increased risk of endometrialhyperplasia and endometrial cancer encountered with oestrogen therapies,the use of oestrogen/progestogen combinations have been utilised.However, these have the common side effects of inducing uterine bleedingand the continuation of menstrual periods.³ Nadelson et al., eds., Treatment Inverventions in Human Sexuality (NewYork: Plenum Press, 1983)

Alternatively, male hormones collectively known as androgens, such astestosterone, and the lack of these in the female body have been linkedto forms of sexual dysfunction. Testosterone is produced in a woman'sbody and the pinnacle of production is generally around the woman'sreproductive years. This production can wane for a variety of reasonsand this waning can be counter-acted in certain instances bytestosterone replacement therapy. In certain cases this counter-actingeffect has prompted an increase in sex drive.

Nevertheless, testosterone replacement therapy carries with it severaldangers analogous to oestrogen replacement therapy and as such is farfrom satisfactory.

Accordingly, it is a general aim of the present invention to provide atreatment for female sexual dysfunction and delivery method for saidtreatment, and specifically the treatment of HSDD, which overcomes orameliorates the problems and drawbacks associated with the prior art aswell as, preferably, overcoming other apparent problems and drawbackswith medicaments for female sexual dysfunction in general.

According to a first aspect of the present invention, there is providedan aroma in the form of at least one dopamine mimetic odorant whereinsaid odorant(s) is capable of causing a physiological effect in, orfrom, the human brain which causes the amelioration of female sexualdysfunction, and particularly the amelioration of HSDD.

The use of an aroma is advantageous since it is capable of actingdirectly on the brain without having to pass through the blood brainbarrier, this is in stark contrast to medicaments which are typicallyadministered by ingestion or intravenously.

The dopamine mimetic ordorants (DMO) of the present invention aredesigned such that they can be sensed by a patient's olfactory systemand act as a stimuli, or binder, to the patient's receptor proteins inthe olfactory tract of the patient's brain to cause the amelioration offemale sexual dysfunction, and particularly the amelioration of HSDD.

Whilst the exact mechanism is far from clear, it is suspected that DMOsof the present invention act in such a way as to initiate a chain ofco-ordinated events in the brain which ultimately lead to changes in thepatient's levels of dopamine and, consequently, the requiredamelioration. However, it is to be understood that the DMOs of thepresent invention may be working quite differently than has beenhypothesised and that the amelioration is achieved by means other thanchanging a patient's level of dopamine in the brain.

It is to be understood that the use of the word dopamine here isintended to include other related neurotransmitters such as epinephrine,norpinephrine and the like.

The DMOs of the present invention are provided in a form capable ofbeing sensed to a patient's olfactory system and comprises at least oneof the following groups of compounds: steroid odorants; amines andrelated molecules; heterocyclic aroma molecules, including Jasmin oil;aromatic molecular mimics of the central neurotransmitter dopamine;carboxylic acids including those which may occur in trace levels inhuman secretions; aldehydes, including those which form traceingredients in odorous human secretions.

Preferably, the DMOs of the present invention comprise at least one ofthe following recognized classes of perfume odorants:—vanillalike—(prototypical example—vanillin); carnation like—(prototypicalexample—isoeugenol); musk like—(prototypicalexample—6,7-dihydro-1,1,2,3,3-pentamethyl-4(5H)-indanone).

Most preferably, the DMOs of the present invention comprise at least oneof the following groups of compounds: vanillin; isoeugenol and acompound in the musk category, preferably the woody musk category.

Ideally, the DMOs of the present invention comprise at least one of thefollowing: ethyl vanillin (3-ethoxy-4-hydroxybenzaldehyde); isoeugenol(2-methodoxy-4-(1-propenyl) phenol; the woody musk6,7-dihydro-1,1,2,3,3-pentamethyl-4(5H)-indanone.

Desirably said carboxylic acids exhibit paradoxical aroma profiles,wherein these profiles combine reassuring odour notes of warm humanflesh but wherein said odour notes are embedded in distinctly fruityodour notes, these odour notes can often serve to prevent the consciousmind apprehending the occult, erogenic odour note. Furthermore saidaldehydes may additionally comprise new synthetic aldehydes which canexhibit a floral odour note with a heart of erogenicity.

According to a second aspect of the present invention, there is provideda range of compound(s) in the form of at least one dopamine mimeticodorant, wherein said odorant(s) is capable of causing a physiologicaleffect in, or from, the human brain which causes the amelioration offemale sexual dysfunction, and particularly ameliorate the effects ofHSDD.

According to a third aspect of the present invention, there is provideda medicament comprising a range of compounds including at least onedopamine mimetic odorant wherein said odorant(s) is capable of causing aphysiological effect in, or from, the human brain which causes theamelioration of female sexual dysfunction, and particularly theamelioration of HSDD.

According to a fourth aspect of the present invention, there is provideda set of formulations comprising at least one dopamine mimetic odorant,wherein said odorant(s) is capable of effecting a physiological effectin, or from, the human brain which causes the amelioration of femalesexual dysfunction, and particularly the amelioration of HSDD.

According to a fifth aspect of the present invention, there is provideda medicament comprising a set of target formulations wherein saidformulations include at least one dopamine mimetic odorant and saidodorant(s) is capable of effecting a physiological effect in, or from,the human brain which causes the amelioration of female sexual disorder,and particularly the amelioration of HSDD.

According to a sixth aspect of the present invention, there is provideda medicament for application to a patient in avoidance of the humanblood brain barrier, wherein said medicament comprises at least onedopamine mimetic odorant and said odorant(s) is capable of effecting aphysiological effect in or from the human brain which causes theamelioration of female sexual disorder, and particularly theamelioration of HSDD.

According to a seventh aspect of the present invention, there isprovided a compound or compounds possessing at least one dopaminemimetic odorant wherein said odorant(s) has an appropriate molecularsize and electrical charge to interact with a neuroreceptor in the humanbrain in such a way as to have an agonistic effect in order to cause theemission of neurotransmitters which cause an effect to the centralnervous system, said effect being a physiological effect which causesthe amelioration of female sexual disorder, and particularly theamelioration of HSDD.

According to an eighth aspect of the present invention, there isprovided a formulation or formulations possessing at least one dopaminemimetic odorant wherein said odorant(s) is capable of interacting with aneuroreceptor in such a way as to have an agonistic effect in order tocause the emission of neurotransmitters which cause and effect to thecentral nervous system, said effect being a physiological effect whichcauses the amelioration of female sexual disorder, and particularly theamelioration of HSDD.

According to a ninth aspect of the present invention, there is provideda dopaminergic agonist(s) in the form of at least one dopamine mimeticodorant, wherein said odorant(s) is capable of causing a physiologicaleffect in or from the human brain to cause the amelioration of femalesexual disorder, and particularly the amelioration of HSDD.

According to a tenth aspect of the present invention, there is provideda natural human odorant comprising at least one dopamine mimeticodorant(s) and/or a synthetic human odorant comprising at least onedopamine mimetic odorant(s) either or both of which are capable ofcausing a physiological effect in or from the human brain which causesthe amelioration of female sexual dysfunction, and particularly theamelioration of HSDD.

According to an eleventh aspect of the present invention, there isprovided a medicament in the form of an aroma comprising at least onedopamine mimetic odorant(s) wherein said aroma has been masked ordisguised such that the at least one dopamine mimetic odorant(s)contained therein is not immediately apparent on application to thepatient, yet capable of causing a physiological effect in or from thehuman brain which causes the amelioration of female sexual disorder, andparticularly the amelioration of HSDD.

According to a twelfth aspect of the present invention, there isprovided an aroma which has a predetermined character as defined by anelectronic nose comprising at least one dopamine mimetic odorant,wherein said aroma is capable of causing a physiological effect in orfrom the human brain which causes the amelioration of female sexualdysfunction, and particularly the amelioration of HSDD.

The at least one dopamine mimetic odorant may be provided in a suitablesolution, such as ethanol, in a concentration up to 40% by volume.Ideally, the concentration is up to 20% by volume. The concentration ofthe at least one dopamine mimetic odorant can vary depending upon whichDMO or DMOs are being used and the delivery means employed.

The aforementioned aspects of the present invention describe the DMOs ofthe present invention. The aspects of the invention mentionedhereinafter describe the delivery systems of the present invention foradministration of the DMOs to a patient.

According to a thirteenth aspect of the present invention, there isprovided a delivery system for any of the at least one dopamine mimeticodorant of the present invention to the patient in the form of a nasalspray. The nasal spray may be administered to the patient by a medicalpractitioner or by the patient themselves. The at least one dopaminemimetic odorant may be present in as a fluid in an appropriateconcentration to be administered to the patient by the form of saidnasal spray. Said nasal spray can comprise a reservoir in operativeconnection with a pump action spray nozzle. The fluid can be housed in areservoir of the nasal spray until it is to be administered to apatient. It is preferably envisaged that the nasal spray will be placedin or near the nasal cavity/cavities of the patient to facilitateadministration of the at least one dopamine mimetic odorant.

According to a fourteenth aspect of the present invention, there isprovided delivery system in the form of a patch which is to be worn bythe patient which is coated or impregnated with the at least onedopamine mimetic odorant. Typically, the patch is adhered to the skin ofthe patient to allow the at least one dopamine mimetic odorant to beemitted therefrom and into the patient via their nasal cavities. Suchpatches are available from The Aromacology Patch Company.

Alternatively, the patch or a strip of patch material may be housed in aprotective sheath, such as a plastic sheath, to allow the insertion ofsame into the nasal cavities of the patient, such that the patient maydraw the active ingredient of the present invention into their nasalcavities via an inhalation of breath through their nasal cavities. It isto be appreciated that the appropriate concentrations of the at leastone dopamine mimetic odorant are to be used in the patch delivery systemand may be included with any other suitable agent to facilitate therelease of said at least one dopamine mimetic odorant into the nasalcavity/cavities of the patient.

According to a fifteenth aspect of the present invention, there isprovided a delivery system for the at least one dopamine mimetic odorantof the present invention which may be applied topically to the patientfor inhalation via the nasal cavities of the patient. Such topicalapplications could be provided in the form of a lipstick or perfume orany other suitable means which are to be applied to the skin and whichare capable of being inhaled by the patient via their nasal cavities.

In order to allow the present invention to be more readily understoodembodiments are described below by way of example.

The most preferred DMOs of the present invention comprise at least oneof the following: ethyl vanillin (3-ethoxy-4-hydroxybenzaldehyde);isoeugenol (2-methodoxy-4-(1-propenyl) phenol; the woody musk6,7-dihydro-1,1,2,3,3-pentamethyl-4(5H)-indanone. In order to determinetheir effectiveness against non-DMOs, a series of formulations wereprepared for testing against a series of standardised controlformulations.

The DMO formulations comprised (all in ethanol solution to 100% byvolume):

-   1. 20% Ethyl vanillin (EV)-   2. 20% Ethyl vanillin (EV) and Isoeugenol (4:1 ratio)-   3. 20% Ethyl vanillin (EV) and Isoeugenol and woody musk    6,7-dihydro-1,1,2,3,3-pentamethyl-4(5H)-indanone-   4. 20% woody musk 6,7-dihydro-1,1,2,3,3-pentamethyl-4(5H)-indanone

The standardised control formulations comprised (all in ethanol solutionto 100% by volume):

-   5. Natural animal cologne-   6. Strong carnation natural perfume-   7. Intensely sweet fruity perfume

The formulations were applied to separate strips of material and thetesters were requested to grade each odour produced on a five-pointscale (A-E). The A end of the spectrum denoting “Like verymuch/including arousal” and E at the other end of the spectrum “Do notlike very much”.

Before the experimentation it was hypothesised that the standardisedcontrol formulations would produce the following response

-   5. Natural animal cologne would produce a significant negative    response, mainly E and D responses.-   6. Strong carnation natural perfume would produce a response roughly    in the middle of the spectrum, mainly C responses.-   7. Intensely sweet fruity perfume would produce a significant    negative response, mainly E and D responses.    Results

The following represent the % of testers grading the odour is marked.

-   1. Majority A or B-   2. Majority A or B-   3. Majority B or C-   4. Majority A-   5. Majority C, D or E-   6. Majority B, C or D-   7. Majority E

Due to numerous inherent limitations in performing tests of this nature,one such limitation being adaptation when forced to test numerous odoursin a short space of time, as well as other well known limitations, it isinteresting to note that the testers graded the standardised controlformulations (5-8) as expected. More interesting however, is that theformulations of the present invention (1-4) all obtained a majority ofthe A end of the spectrum, denoting “Like very much/including arousal”.

Of course numerous modifications and variations are envisaged with theformulations, compounds, aromas, medicaments or dopamenic agonists ofthe present invention and these will be apparent to the skilled personwithout need to depart from the invention.

1-19. (canceled)
 20. A formulation comprising a vanilla like odorant, acarnation like odorant and a musk like odorant.
 21. A formulationaccording to claim 20 comprising up to 40% (by volume) of a vanilla likeodorant up to 40% (by volume) of a carnation like odorant up to 40% (byvolume) of a musk like odorant
 22. A formulation according to claim 20comprising up to 20% (by volume) of a vanilla like odorant up to 20% (byvolume) of a carnation like odorant up to 20% (by volume) of a musk likeodorant
 23. A formulation according to claim 20 wherein the vanilla likeodorant is a vanillin.
 24. A formulation according to claim 20 whereinthe vanillin is ethyl vanillin.
 25. A formulation according to claim 20wherein the carnation like odorant is isoeugenol.
 26. A formulationaccording to claim 20 wherein the musk like odorant is a woody muskodorant.
 27. A formulation according to claim 26 wherein the woody muskodorant is 6,7-dihydro-1,1,2,3,3-pentamethyl-4(5H)-indanone
 28. Aformulation according to claim 20 comprising 1-19% (by volume)3-ethoxy-4-hydroxybenzaldehyde up to 5% (by volume)2-methoxy-4-(1-propenyl) phenol 1-19% (by volume) 6,7-dihydro-1,1,2,3,3-pentamethyl-4(5H)-indanone
 29. A formulation according to claim20 further comprising a carboxylic acid.
 30. A formulation according toclaim 29, which exhibits paradoxical aroma profiles.
 31. A formulationaccording to claim 30 wherein the paradoxical aroma profiles combineodour notes of warm human flesh embedded in fruity odour notes.
 32. Aformulation according to claim 20 further comprising syntheticaldehydes, which exhibit a floral odour note with a heart oferogenicity.
 33. A formulation substantially as herein described.
 34. Askin patch comprising a formulation according to claim
 20. 35. A nasalspray comprising a formulation according to claim 20
 36. A lipstickcomprising a formulation according to claim
 20. 37. A perfume comprisinga formulation according to claim
 20. 38. A delivery device in the formof a strip of material housed in a protective sheath coated orimpregnated with a formulation according to claim
 20. 39. A deliverydevice according to claim 38, wherein the protective sheath is providedwith suitable closure means to control the release of the formulationfrom the sheath.
 40. The use of a formulation according to claim 20 forthe treatment of female sexual dysfunction.
 41. A method of treatingfemale sexual dysfunction comprising administering to the olfactorysystem of a patient, an effective amount of the formulation disclosed inclaim
 20. 42. A method of treating female sexual dysfunction accordingto claim 41 wherein the formulation is administered to the patient byapplication to the patients skin of a patch, which is coated orimpregnated with the formulation.
 43. A formulation according to claim20 for use in the treatment of female sexual dysfunction.
 44. The use ofa formulation according to claim 20 in the production of a medicament ofthe treatment of female sexual dysfunctions.